Phosphodiesterase-4 (PDE4), an enzyme that hydrolyzes cyclic AMP (cAMP), plays the major role in the control of intracellular cAMP concentrations, particularly in neurons in the brain. The level of the cAMP-protein kinase A (PKA) signaling cascade in the brain has been found inversely correlated with that of ethanol consumption in animal models. Given that inhibition of PDE4 enhances cAMP/PKA signaling, we hypothesize that PDE4 is a novel target for drugs that decrease ethanol consumption; inhibition of PDE4 reduces ethanol drinking. Our long-term goal is to develop novel, potent agents to treat alcoholism. The objectives of this proposal are to establish PDE4 as a viable target to reduce ethanol consumption. Therefore, we will first determine whether PDE4 inhibition decreases ethanol consumption. This will be accomplished by examining the effect of rolipram, a prototypical inhibitor of PDE4, on ethanol consumption in well recognized animal models of excessive alcohol drinking, including C57BL/6J mice and high alcohol-preferring mice (HAP2 and HAP3 lines). PDE4 activity and expression in brain regions of interest will be examined in HAP and low alcohol preferring (LAP) mice to see whether PDE4 is relevant in the genetic determination of ethanol preference. We will then examine the effect of rolipram on ethanol motivation using conditioned place preference (CPP) and conditioned taste aversion (CTA) tests in mice. Finally, we will further identify the role of PDE4 subtypes in the regulation of ethanol consumption using the two-bottle choice test in mice deficient in PDE4A, PDE4B, or PDE4D. Successfully completion of these experiments will not only establish the role of PDE4 in the regulation of ethanol consumption, but also identify PDE4B, which is the only PDE4 subtype expressed in the striatum and amygdala, as the major PDE4 subtype responsible for regulating ethanol consumption. The latter is particularly important given that PDE4B is not involved in nausea and emesis, the primary side effects of PDE4 inhibitors. The outcomes of the proposed studies will encourage and accelerate the development of selective inhibitors of PDE4B as novel treatment for alcoholism, which affect 18 million Americans. Therefore, the issue expected to be resolved in this proposal is of importance and considerable relevance to public health.